Retinopathy of prematurity (ROP) is a vasoproliferative retinal disease that afflicts as much as 60% of all extremely low gestational age neonates (ELGANs, <1250g/<28 weeks) with approximately 5% condemned to a lifetime of blindness. Caffeine and NSAIDs have already been shown to decrease the risk of severe ROP in ELGANs. We propose a novel approach of combining topical ketorolac or systemic ibuprofen with systemic caffeine to optimize their efficacy for prevention of ROP. The overarching goal of this proposal is to investigate the synergistic effects of NSAIDs potentiated with systemic caffeine on the incidence and severity of ROP. Our specific aims are three-fold: 1) To establish the synergistic effect of local ophthalmic NSIADs and systemic caffeine as optimal therapies for the attenuation and/or prevention of severe ROP. We hypothesize that ocular ketotolac or systemic ibuprofen potentiated with systemic caffeine will prevent or diminish the severity of ROP; 2) To identify a critical number of arterial oxygen desaturations as a key risk factor for severe ROP. We hypothesize that there is a critical number of daily arterial oxygen desaturations experienced by ELGANs during the first two weeks of life that is a key risk factor for severe ROP; and 3) To determine whether infants at risk for severe ROP are haploinsufficient for the delta-like ligand 4 (D114). We hypothesize that ELGANs at risk for severe ROP will have different pattern of gene expression specifically related to the Notch signaling pathway, as has been previously shown in animal models. We will use gene profiling to determine whether haploinsufficiency of DII4 is associated with severe ROP. We will use state-of-the-art technologies to provide insights on the biomolecular mechanisms associated with ROP. We have all the necessary technologies and systems in order to successful accomplish these proposed works.